THE  RELATION  BETWEEN  PHYSICAL  PROPERTIES  AND 
PHYSIOLOGICAL  ACTION  OF  CERTAIN 
LOCAL  ANESTHETICS 


WALDO  BRIGGS  BURNETT 
A.  B.  Southern  Methodist  University,  1919 


THESIS 


Submitted  in  Partial  Fulfillment  of  the  Requirements  for  the 


Degree  of 


MASTER  OF  SCIENCE 


IN  CHEMISTRY 


IN 

THE  GRADUATE  SCHOOL 
OF  THE 

UNIVERSITY  OF  ILLINOIS 
1921 


\^2-\ 

UNIVERSITY  OF  ILLINOIS 


THE  GRADUATE  SCHOOL 


% 


Jung  3, 1 92I— 


I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 


SUPERVISION  BY 


ENTITLED THE  RELATION  'BETWEEN  PHYSICAL  PROPERTIES  AIID 

PHYSIOLOGICAL  ACTION  Off  CERTAIN  LOCAL  ANESTHETICS 

BE  ACCEPTED  AS  FIJLEILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 
THE  DEGREE  OF  _ 


Head  of  Department 


Recommendation  concurred  in* 


Committee 

on 

Final  Examination* 


*Required  for  doctor’s  degree  but  not  for  master’s 


, 


TABLE  OF  CONTENTS 

I INTRODUCTION 1 

II  THEORETICAL  PART 3 

Theories  of  Anesthesia  . 3 

Asphyxiation  theory  3 

Catalase  theory . . . . . 3 

Valence  theory 3 

Permeability  theory  4 

Lipoid  hypothesis  4 

Jkethods  for  the  Synthesis  of  Novocaine 6 

^ Di-n-Buty  1 Amino- Ethyl  p-Amino  Benzoate  Monohydrochloride9 

Preparation  of  Secondary  Amines * 9 

Hofmann  method 9 

Anilin  method 10 

Sulfonamide  method 10 

Cyanamide  method 11 

Preparation  from  ketones 11 

Preparation  from  ketoximes  and  aldoximes.  ......  11 

Preparation  from  nitriles 11 

Preparation  from  alcohol  and  ammonia.  ........  12 

Degradation  of  tertiary  amines.  ...........  12 

p-Nitroso  di-n-Buty  1 Aniline  Hydrochloride 13 

Di-n-Buty  1 Amine . 13 

P Di—n— Butyl  Amino  Ethyl  Alcohol  16 

Ethylene  Oxide  . ........  17 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/relationbetweenpOObu 


p-Nitrobenz oyl  Chloride  . • . * * 17 

/3 -Di-n-Butyl  Amino  Ethyl  p-Uitr o Benzoate  Hydro chloridel8 


ft  -Di-n-Butyl  Amino  Ethyl  p-Amino  Benzoate  Monohydro- 
chloride   IS 

ft  -Biisobutyl  Amino  Ethyl  p-Amino  Benzoate  Monohydro- 
chloride   .....  19 

Diallyl  Amine  21 

Y'  Bromopropyl  p-Nitrobenz  oate 21 

III  EXPERIiiffiNTAL  PART 23 

p-Nitr os  o-di-n-Butylaniline  Hydrochloride  23 

Di-n-Butyl  Amine 24 

Ethylene  Oxide 23 

^Bi  -n-Butyl  Amino  Ethyl  Alcohol 26 

/9  Di-n-Butyl  Amino  Ethyl  p-Mitrobenzoate. hydrochloride.  27 

ft  Di-n-Butyl  Amino  Ethyl  p-Amino  benzoate  Monohydrochlor- 
ide   28 

Diisobutyl  Amine 29 

/^Diisobutyl  Amino  Ethyl  Alcohol . 29 

ft  Di iso’outyl  Amino  Ethyl  p-Nitrobenzoate  Hydrochloride  JO 

ft  Diisobutyl  Amino  Ethyl  p-Amino  benzoate  Monohydrochlor- 
ide 30 

)T  Bromopropyl  p-Nitrobenzoate  30 

Unsuccessful  Attempts  to  Prepare  Secondary  Amines  ...  31 

Di  isobutyl  aniline 31 

p-Nitroso  diisobutyl  aniline  hydrochloride 32 

Diisoburyl  amine . 32 

Diallyl  amine.  32 

Di-n-butyl  ainine  by  the  sulfonamide  method  ....  32 

IV  SUMMARY 34 

V  BIBLIOGRAPHY 33 


THE  RELATION  BETWEEN  PHYSICAL  PROPERTIES  AND  PHYSIO- 
LOGICAL ACTION  OF  CERTAIN  LOCAL  ANESTHETICS. 

I INTRODUCTION. 

The  literature  contains  numerous  articles  which  point  out 
the  relationship  existing  between  the  structure  and  the  physio- 
logical action  of  various  local  anestnetics.  Other  articles 
point  out  the  relationship  between  the  structure  and  the  physi- 
cal properties  but  there  are  few  which  attempt  to  correlate 
these  three  properties  and  draw  definite  conclusions  from  the 
same . 

This  research  was  undertaken  in  an  effort  to  arrive  at 
some  such  conclusions.  In  order  that  the  results  may  be  as  in- 
clusive and  the  conclusions  as  general  as  possible  it  is  planned 
to  prepare  a series  of  the  monohydrochlorides  of  the  dialkylamino 
ethyl» propyl,  butyl,  and  anyl  esters  of  p-amino  benzoic  acid. 

The  alkyl  groups  will  be  methyl,  ethyl,  propyl,  isopropyl,  butyl, 
isobutyl,  amyl,  isoamyl,  allyl,  heptyl  and  lauryl. 

It  is  probable  that  the  entire  series  of  the  higher  esters 
such  as  the  dialkylamino  butyl  and  amyl  esters  will  not  be  pre- 
pared; only  a few  representative  ones;  in  order  that  their  re- 
lation to  the  members  of  the  lower  series  may  be  determined. 

Various  physical  constants  such  as  meltiiig  point,  refractive 
index,  specific  gravity,  soluoility,  lipoid-water  partition  coef- 
ficient and  the  effect  upon  surface  tension  will  be  determined. 

The  pharmacological  tests  will  be  made  elsewhere  and  re- 


ported later 


-2- 


j?rom  the  data  obtained  it  is  hoped  that  certain  conclusions 
may  be  drawn  as  to  the  effect  of  certaiii  types  of  side  chains 
upon  the  anesthetic  properties  and  the  toxicity  of  the  compounds 
studied.  Because  of  the  different  types  that  will  be  prepared 
it  will  be  possible  to  study  the  effect  of  a straight  or  forked 
side  chain,  and  a saturated  or  unsaturated  side  chain  in  addition 

to  the  effect  of  the  mere  weight  of  tne  chain  alone. 

1 2 

Jenkins  and  Peet  , who  are  working  upon  different  phases 
of  this  same  general  problem  have  prepared  and  studied  certain 
members  of  tnese  series,  namely  the  monohydrocnlorides  of  ft  di- 
methyl, ft  di-n-propyl,^  di isopropyl  and  ft  di-n-amyl  amino 
ethyl  and  Y diethylamino  propyl  esters  of  p-amino  benzoic  acid. 
This  paper  will  treat  only  of  the  monohydr ochlorides  of  the/^7  di- 
n-butyl and  ft  diisobutyl  amino  ethyl  esters  of  p-amino  benzoic 
acid.  Other  members  of  these  series  will  be  prepared  and  studied 
at  a later  date. 


.. 


. 


• ' - “ •* 
» . 


v‘ 


4 


■ .. 


i 


. 


-3- 


II  THEORETICAL  PART 

A great  number  of  theories  have  been  advanced  from  time 
to  time  in  an  effort  to  explain  the  phenomena  of  local  anes- 
thesia. No  set  of  experiments  has  ever  proven  definitely  that 
any  particular  theory  is  correct  and  the  real  cause  of  local 
anesthesia  is  still  a matter  of  some  conjecture.  The  mere  nature! 
of  the  problem  limits  the  research  largely  to  a process  of  trial 
and  error  and  a theory  that  appears  to  hold  for  one  set  of  con- 
ditions does  not  hold  for  a different  set  of  conditions.  A 
brief  explanation  of  some  of  the  more  important  theories  will 
tend  to  show  the  exact  state  of  affairs  as  they  stand  today. 

3 

(1)  The  asphyxiation  theory.  Verworn  advances  tne  theory 
that  anesthesia  is  produced  because  the  cell  is  prevented  from 
carrying  out  its  normal  oxidation  processes.  The  cell  remains 
dormant  as  long  as  these  oxidation  processes  are  prevented. 

There  is  no  doubt  that  oxidation  is  prevented  to  some  extent, 
but  as  some  have  pointed  out,  there  is  a question  as  to  whether 
this  decrease  is  the  cause  or  result  of  anesthesia. 

4 

(2)  Tne  catalase  theory.  This  theory,  held  by  Burge  of 
the  University  of  Illinois,  is  similar  to  that  of  Verworn  except 
that  the  decrease  in  oxidation  is  supposed  to  be  due  to  the  ac- 
tion upon  the  enzyme  catalase.  Burge  thinks  that  the  anesthetic 
either  destroys  or  inhibits  the  action  of  the  enzyme.  Naturally 
the  same  objections  that  hold  for  the  preceding  theory  will  hold 
for  this  one  also. 

6 

(3)  The  valenc  e theory . Mathews  believes  that  both  the 


-4- 


anesthetic  and  the  protoplasm  of  the  cell  possess  residual  val- 
ency and  a union  of  the  two  produces  anesthesia*  He  considers 
the  irritable  substance  in  protoplasm  to  be  an  oxygen  protoplasm 
compound.  Normal  stimulation  produces  oxidation  with  the  con- 
sequent rearrangement  of  this  more  or  less  unstaole  compound 
and  the  liberation  of  carbon  aioxide.  The  presence  of  an  anes- 
thetic prevents  this  action  oecause  it  forms  a noil-irritable, 

dissociable  compound  with  the  protoplasm. 

e 

Ehrlich  upholds  this  theory  and  adds  to  it  the  idea  of 
certain  haptophoric  groups  which  make  the  union  of  anesthetic 
and  protoplasm  easier.  He  considers  NHa  as  the  nighest  of  these 
groups. 

(4)  The  permeability  theory.  Lillie  contends  that  anes- 
thesia effects  the  permeability  of  the  cell.  This  is  quite 
likely,  because  the  effect  of  an  anesthetic  is  essentially  physi- 
cal in  nature,  effecting  the  inter surface  activities  especially. 

a 9 

Osterhout  agrees  with  this  theory  while  Harvey  opposes  it. 

10  11 

Traube  and  Clowes  , in  turn,  disagree  with  the  work  of  Harvey 
and  uphold  Lillie's  theory. 

i; 

(5)  The  lipoid  hypothesis.  Although  this  theory  of  Overton 
and  Meyer  does  not  attempt  to  explain  definitely  the  cause  of 
local  anesthesia  it  does  in  a way  attempt  to  explain  the  mechan- 
ics of  anesthesia.  The  nerve  cexls  which  are  effected  by  the 
anesthetic  contain  the  lipoid,  lecithin  and  the  wax,  cholesterol 
in  considerable  amounts. 

The  anesthetic  strength  of  a compound,  has  been  proven,  in 
a qualitative  way  at  least  to  be  a function  of  its  distribution 


-5- 


between  blood  and  oil.  In  experimental  work  water  takes  the 
place  of  blood. 

Prom  a study  of  these  theories  it  will  be  seen  that  this 
worm  is  still  in  its  earliest  experimental  stages.  However, 
it  does  seem  logical  that  a lipoid-water  partition  coefficient 
w'ould  give  some  indicati on, probaoly  quantitative,  as  to  the  an- 
esthetic strength  of  these  substances. 

Since  the  free  bases  of  these  anesthetics  are  water  insol- 
uble the y must  be  administered  as  salts.  The  rate  at  which  they 
take  effect  should  depend  upon  their  rate  of  hydrolysis  if  we 
are  to  assume  that  they  hydrolyze  and  then  the  free  base  is  ab- 
sorbed by  the  lipoidal  substance  of  the  cell.  It  would  also 
depend  in  part  upon  the  rate  at  which  the  free  base  is  absorbed. 

As  has  been  seated  before  all  of  the  anesthetics  that  are 
to  be  considered  in  this  work  are  benzoic  acid  esters.  The 
amine  group  in  trie  ring  serves  only  to  neutralize  the  acid  prop- 
erties of  the  acid  salt  of  the  amine  group  in  the  side  chain. 
This  reduces  tne  irritating  effect  of  the  anesthetic  to  a mini- 
mum. 

It  is  rather  interesting  to  none  their  structural  relation 
to  the  natural  anesthetic  cocaine. 


H 


.0 


C - OCR  - CHa 
Coca  ine 


:ch 


- OCHaCKatf< 


a 


CH  - kT  - CHs 


UHa 


-6- 


13 

Einhorn  early  suggested  that  allbenzoic  acid  esters 
possessed  anesthetic  properties  of  a greater  or  less  degree. 
Working  upon  this  theory  he  soon  succeeded  in  preparinga  con- 
siderable number  of  esters  which  possessed  anesthetic  proper- 
ties but  tneir  insolubility  made  their  use  very  unsatisfactory, 
so  he  next  undertook  the  preparation  and  study  of  the  alkamino 
esters . 


Ke  found  that  the  alkamino  esters  showed  anesthetic  proper- 
ties but  these  were  not  so  marked  as  those  of  cocaine.  However, 
/}  di et tylamino  ethyl  p-anino  benzoate  hydrochloride,  known  to 
the  trade  as  "procaine”  or  "novocaine"has  come  into  general  use 
because  its  low  toxicit3r  makes  it  superior  to  cocaine  although 
its  anesthetic  power  is  not  as  great  as  that  of  cocaine. 

14 

Adams  and  Kairnn  have  worked  on  the  various  methods  for 
preparing  "novocaine"  and  have  succeeded  in  synthesizing  a relat- 
ed compound  that  has  proven  much  superior  to  "novocaine"  in 
actual  practice.  It  is  the  nydrosulfate  of  T di  -n-outyl  amino 
propyl  ester  of  p-amino  benzoic  acid  and  is  known  to  the  trade 
as  "butyn" . 

All  of  the  methods  for  the  synthesis  of  these  various  anes- 
thethics  are  methods  that  have  been  used  for  the  synthesis  of 
novocaine.  Einhorn  used  them  with  varying  success.  The  various 
methods  are  represented  by  the  following  equations: 


(1)  (a) 


>C  - Cl 

+ HOCHaCHaNN^ 


HO  2 


,o  h cir 

C - 0 - CHaCHafrCR 


Fe 


HO  a 


in  . si  ^ ■.  ■ 1 


• - * 


■ . 

i. 

. . » 


> ** 


... 

V b 

. 

, . ..  x ■ . 


. . 


. . . 


, 


:»  • 


* 


: . 


. 


4 » 


• i i ' 


. 


i *■ 


-8- 


(4) 


(5) 


0 

c"-  0 


JR 


- CHaCHaN^ 


C - OCHaCHaMV  HC1 


NHa 


0 H Cl_ 

6 - OCKaCHa^<^ 


9 

C - OCaHe 


+ H0CH3  CHaN 


P 

<— C - OCHaCHaH 


NO  3 


(f  - 0 - CHaCHaN^  EC1 


9 T H> c; 

aC  — OCEa  CHa  — VT, 
NHa 


Each  of  the  above  methods  may  be  varied  by  reducing  to 
the  amino  acid  in  the  first  place  and  then  carrying  out  the 
other  reactions.  These  are  all  general  methods  and  will  apply 
for  the  preparation  of  the  dialkyl,  propyl,  butyl  and  arayl  esters 

The  processes  may  be  varied  still  further  by  using  differ- 
ent methods  for  the  preparation  of  the  secondary  amines  and 
alcohols.  There  are  a variety  of  ways  for  reducing  the  nitro 
group  to  an  amino  group.  These  various  methods  will  be  discuss- 
ed later. 

method  (1)  has  been  used  in  the  synthesis  of  both  of  the 
esters  to  oe  discussed  in  this  tnesis  and  will,  be  discussed 
more  in  detail  later.  The  reason  for  its  adoption  was  tnat  most 
of  the  reactions  involved  went  smoothly  and  gave  good  yields. 

Method  (2)  was  not  used  because  it  does  not  go  so  smoothly 
and  the  reactions  are  more  difficult  to  control.  However  it 


-9- 

does  go  fairly  well  with  members  of  the  \ dialkamino  propyl 
ester  series  and  probably  will  be  adopted  as  the  standard  method 
for  their  syntnesis. 

Method  (3)  is  similar  in  several  respects  t o method  (2), 
but  does  not  give  such  good  yields.  The  chief  objection  is 
that  it  includes  an  autoclave  reaction  and  as  a rule  these  reac- 
tions give  poor  yields  . 

Method  (4)  is  of  theoretical  interest  out  of  210  practical 
importance.  Very  poor  yields  are  obtained  and  it  is  very  doubt- 
ful that  it  will  ever  be  developed  t 0 any  considerable  degree. 

The  same  may  be  said  for  method  (3)  in  which  even  poorer 
yields  are  ootained. 


ft  Bi-n-Eutvl  Amino  Ethvl  p -Amino  Benzoate  Monohvdr och^r id e 

The  interned iate  which  gave  the  most  difficulty  in  prepara- 
tion was  di-n-butyl  amine.  Since  this  is  almost  universally  the 
case  it  will  be  well  to  tabulate  in  a brief  way  some  of  the 
methods  for  the  preparation  of  secondary  aliphatic  amines.  One 
thing  is  quite  evident  from  a study  of  tnese  metnods,  namely 
many  of  them  are  by  no  means  what  might  be  considered  general 
methods.  Another  outstanding  fact  is  that  the  yields  are  always 
quite  poor  and  fully  fifty  per  cent  of  the  investigators  never 
report  yields,  being  content  to  merely  mention  the  fact  that 
they  obtained  trie  product  in  sufficient  quantities  to  be  isolat- 
ed. 

Preparation  of  Secondary  Amine s . 

16 

(1)  Hofmann  method.  Tnis  was  first  used  by  Hofmann  in 


1849  and  since  that  time  ha 


s oeeu  varied  in  some  of  its  minor 


-10- 


details  by  scores  of  investigators.  In  its  simplest  form  it 
consists  of  heating  an  aliphatic  halogen  compound  with  ammonia, 
in  e ither  an  aqueous  or  alcoholic  solution. 

RX  + NH3  *•  RNHa  + HX 

RNHa  + RX *■  RaNH  + HX 

RaNH  + RX *RaN  + HX 

The  chief  objection  is  that  a mixture  of  primary,  secondary 

and  tertiary  amines  is  obtained  and  except  in  unusual  cases  the 

1 e 

yield  of  the  secondary  amine  is  very  low.  Van  der  Zande's 
modification  in  which  he  uses  a 15  per  cent  solution  of  ammonia 
in  alcohol  was  found  to  be  the  best  method  of  this  type. 

1 7 

(2)  Aniline  method.  This  method  as  developed  by  Reilly 
and  Hickinbottom  and  other  investigators  works  quite  satisfactor 
ily  and  has  the  advantage  of  giving  only  pure 'secondary  amines. 
The  yields  fall  off  very  materially  with  an  increase  in  the 
number  of  carbon  atoms  in  the  amine. 


(3)  Sulfonamide  method.  This  method,  developed  by 

ia 

Marckwald  and  Freiherr  works  well  for  the  lower  amines  but  not 
so  well  for  the  higher  ones.  The  equations  are  self  explanatory 
RSO2NH2  + 2NaOH  + 2R ' Cl  *R  SOaNR'a  + 2NaCl  + 2Ha  0 

RSOaNR'a  + S0a<°?*  *RS02C1  + S03<°g3  , 

S02<CE  + H2O  ^so3<0ii  + HNR*a 

NRa  » OH 


-Il- 


ls 

(4)  Cyanamide  method . Traube  and  Engelhardt  obtained  60 
per  cent  yields  of  d imethylamine  in  this  way  but  the  yields  of 
the  higher  amines  were  much  smaller.  It  has  the  advantage,  like 
the  preceding  one  of  being  a very  cheap  process. 

HC1 


CaHC H + R3SO4 


0*4 


■RaHCH  + CaS04 


lClC 


RaiRCOO;  H >RaHH 


NasHCK  + 2 HI 

RaNlSoS}  H 


la  HCH  + 2 Had 
-HRaHH 


(5)  Preparation  from  ketones.  This  method  as  developed  by 

30 

Lftffler  is  suitable  for  the  preparation  of  either  normal  secon- 


dary amines  or  mixed  amines 

A3 


X1>c<® 


+ Xl>c 

Xz' 


Xi 

Xa>c— RHR 


HR  Ha  y ^ i^CHHHR 

Ha  + alcohol  Xa 


(6)  Preparation  from  ketoximes  and  aldoxiines . The  catalytic 

3 1 

hydrogenation  method,  reported  by  Mailhe  gives  about  one  third 


of  the  primary  and  two-thirds  of  the  secondary  amine. 
R - C - R 

II 

HOH 


+ Ha 


Hi 


1500  - 200^  VR 


*■  ( R >CH  )a  HH  + Ha  0 


Copper  may  be  used  as  a catalyst  instead  of  nickel. 

(7)  Preparation  from  nitriles.  This  method  of  Sabatier 

and  Sender ens  is  quite  similar  to  fhe  preceding  one. 

Hi 

Cn  Han  + 1 + 2H2  1800  22  0^  * + 1 « CHa HHa 


a 2 


2CnH3n  + 1 • CHa .HHa 


HHs  + ( CuHan  + iCHa  )sHH 


(CnHan+1  .CH2)aira  + CuH3u+1 


CHa  HHa 


*>HH3+(  CjiHa^i+x  ‘CHa  )sH 


. . 


1 


1 . . 


' 


- 


• ' 


: 


*•  • . 





- : . . 


-12- 

(8)  (a)  Catalytic  preparation  from  alcohol  and  ammonia. 

3 3 

This  method  as  reported  by  Sabatier  and  Mailhe  gives  rather 

low  yields  of  a mixture  of  primary  and  secondary  amines. 

TnOo  or  W 03.  „ Tr  ^ 

RQH  + NH3  o_  _)70°  + HaO 

ROH  + RNHa *-RaNH  + HaO 


(b)  This  method  has  been  slightly  changed  by  Merz  and 
Gasiorowski  who  carry  it  out  in  an  autoclave  in  the  presence  of 
zinc  cnloride 


Small  yields  are  obtained. 

(9)  Degradation  of  tertiary  amines. 

3 5 

(a)  Yon  Braun's  method  is  intended  primarily  for  the  syn- 
thesis of  rather  complex  amines  but  should  work  likewise  for 
simple  aliphatic  amines. 


(b)  Another  degradation  method  that  nas  been  developed  oy 

2 6 

Bayer  and  Company  for  the  preparation  of  dimethyl  amine  should 
be  general  in  its  application 

RsN.HCl  + 2NaOCl *- 

RaN.Cl  + CHaO  + 2NaCl  + HaO 

\2im  + hci 


Other  methods  for  the  preparation  of  secondary  amines  have 


2 4 


16  hours 


ROH  + RNHa 


*-RaNH  + HaO 


been  reported  but  tney  are  suited  only  for  specific  amines  and 
are  not  general  in  their  application,  c onsequerrcly  they  will  not 


-13” 


be  discussed.  Notable  among  these  is  the  formaldenyde  ammonium 

2 7 

chloride  method  of  Werner  for  the  preparation  of  dime thy lamine. 

p-Nitros  odi-n-3utyl  Aniline  Hvdr  oc  hlor ide 

The  reaction  for  this  preparation  is  a general  reaction  for 

the  nitrosation  of  substituted  anilines,  molecular  quantities  of 

sodium  nitrite  are  added  to  a solution  of  di-n-butyl  aniline  in 

two  and  a half  moles  of  hydrochloric  acid.  The  reaction  mixture 

must  be  well  stirred  and  tne  yields  are  cut  down  if  the  tempera- 

o 

ture  rises  above  3 • Under  these  conditions  90  per  cent  yields 
were  easily  obtained. 


If  this  compound  is  to  oe  stored  for  any  length  of  time  it 
should  be  stored  as  the  free  base  and  not  as  the  hydro  chloride 


because  the  latter  partially  decomposes  into  a tarry-like  mass 


Di-n-Butvl  Amine 

1 7 

Since  Reilly  and  Hickinbottom  claimed  100  per  cent  yields 


of  di-n-butyl  amine  by  the  aniline  method  it  w as  decided  to  use 


R Cl 


Below 


upon  continued  stand ing. 


that  method. 


H Cl 


I'  } 


- 


. 


!•»  - V 


V V • \ 


■ - 

• 

. 

. 

• 

. 

- . . : 


-14- 


The  nitroso  group  in  the  ring  para  to  ohe  amino  group  acti- 
vates it  so  that  it  may  be  easily  nydrolyzed  off.  This  is  in 
accordance  with  the  general  behavior  of  the  nitrosP  and  nitro 
groups  • 

The  exact  method  as  reported  by  Reilly  and  Hickinbottom 
was  to  reflux,  for  three  hours  the  p-nitroso-di-n-butyl  aniline 
hydrochloride  with  an  excess  of  10  pe r cent  sodium  hydroxide 
solution.  The  reaction  mixture  was  then  steam  distilled  and 
the  amine  collected  in  hydrochloric  acid.  The  free  nitroso 
base  may  be  hydrolyzed  in  a similar  way  but  it  was  not  used 
because  it  was  an  oil  and  was  not  as  easy  to  handle  as  hhe 
hydrochloride. 

The  exact  directi cns  as  given  were  carried  out,  using  a 
thirty  gram  sample  but  instead  of  a 100  per  cent  yield  a 5*5 
per  cent  yield  was  obtained.  A tar-like  material  was  formed 
in  the  reaction  mixture,  resulting  most  likely  from  the  action 
of  the  concentrated  alkali.  The  nitroso  compound  had  been 
freshly  prepared  so  decomposition  could  not  have  taken  place 
previously.  A thirty  gram  sample  was  used  in  all  of  these  pre- 
liminary runs  while  the  above  investigators  only  made  one  run 
with  a nine  gram  sample.  Evidently  they  are  in  error. 

In  an  effort  to  prevent  this  tar  formation  more  dilute  solu- 
tions of  the  alkali  were  used  and  the  time  of  refluxing  was 
lengthened.  Wien  a half  mole  excess  of  5 pe r cent  sodium 
hydroxide  was  used  and  the  mixture  refluxed  for  six  hours  a 33 
per  cent  yield  was  obtained. 

Refluxing  with  exact  molecular  proportions  of  the  alkali  in 


-15- 


5 per  cent  solution  gave  only  traces  of  amine.  Another  varia- 
tion tried  was  starting  distillation  immediately  instead  of  re- 
fluxing. The  concentration  was  kept  constant  by  adding  water 
through  a dropping  funnel  as  rapidly  as  it  distilled  out.  Very 
little  if  a ty  amine  was  formed  in  this  reaction. 

A. 1 per  cent  solution  of  sodium  hydroxide  was  tried  but 
without  much  success.  Apparently  trie  splitting  process  went  on 
smoothly  but  slowly.  The  large  volume  of  water  made  it  diffi- 
cult to  isolate  all  of*  the  amine. 

A 2 l/2  solution  of  sodium  hydroxide  was  next  use  d and 
after  refluxing  for  twelve  hours  a 41  per  cent  yield  was  obtain 
ed.  On  subsequent  runs  this  yield  was  increased. to  47*5  per 
cent.  These  figures  are  for  pure  amine  and  not  for  the  crude 
product. 

The  method  of  absorption  in  hydrochloric  acid  was  abandon- 


ed in  favor  of  distillation  through  a Clarke  separator.  The 
objection  to  absorption  in  hydrochloric  acid  was  that  the  pro- 
duct was  very  difficult  to  dry  and  a second  operation  was  neces- 
sary to  obtain  the  pure  amine. 


The  sulfonamide  method  for  the  preparation  of  di-n-butyl 
amine  was  also  attempted  out  was  not  satisfactorily  completed. 
The  chief  advantage  of  this  method  is  that  all  of  the  interme- 
diates are  relatively  cheap.  Tne  equations  are:- 


28 


-16- 


The  reason  that  this  method  was  abandoned  was  tnat  the  sub- 
stituted tolyl  sulfonamide  is  difficult  to  purify  by  distilla- 
tion even  under  diminished  pressure  because  of  the  great  ease 
with  which  it  chars  and  decomposes.  A further  and  greater  dif- 
ficulty is  the  hydrolysis  of  the  substituted  tolyl  sulfonamide 
to  obtain  the  secondary  amine. 

f3  Di-n-Butvl  Amino  Ethvl  Alcohol 
There  are  two  good  methods  for  the  preparation  of  this  com- 
p.ound,  both  of  which  are  in  actual  practice  commercially  for  the 

29 

preparation  of  related  alcohols.  They  are  the  chlorohydrin 

method  and  a modification  of  the  ethylene  oxide  method  as  report- 
3 o 

ed  by  Matches  . 

The  ethylene  chlorohydrin  method  gives  only  about  a 50  per 
cent  yield  but  the  amine  that  does  not  react  may  be  recovered. 

The  chief  objection  is  that  continued  refractionation  is  neces- 
sary in  order  to  get  a pure  product.  A large  excess  of  ethylene 
chlorohydrin  must  be  used. 

C4H9>NH  + G1CHaC^  0H  — C4H9>NCHaCHa0H  + HC1 

The  ethylene  oxide  method  is  the  oetter  method  of  the  two 
because  it  runs  smoothly  and  gives  practically  quantitative 
yields.  Mathes ’method  is  varied  by  heating  the  etnylene  oxide 
and  dibutyl  amine  in  a sealed  tube  in  the  water  bath  for  twelve 
to  fifteen  hours.  The  reaction  will  not  go  if  both  of  the  react- 
ing substances  are  entirely  dry.  It  was  found  that  ethylene 
oxide  prepared  in  the  usual  way,  if  not  previously  dried,  con- 
tained enough  moisture  for  this  purpose.  The  reaction  will  also 


„ . t.  * • 


. ' 

. 

' 


..... 

• ■ v •'  *•  ’ 

. 

- 

V • t 

v 

. ' . . . ...  i.  ' ' 

V \ ' - t ' r 

W ■ . - 3 .^1  > •<*  - - 

* 


‘ i 


-17- 


go  to  completion  if  x-he  reacting  substances  are  allowed  to  stand 
in  contact  with  each  other  for  several  days. 

Bthvlene  Oxide 

Ethylene  oxide  may  oe  prepared  by  treating  ethylene  chloro- 

3 1 

hydrin  with  sodium  hydroxide 


CHa  - CHa 
Cl  OH 


HaOH 


+ HC1 


50  per  cent  yields  are  obtained  by  this  method.  A consid- 
erable quantity  is  lost  during  condensation  because  of  its  low 
boiling  point.  It  may  be  kept  quite  satisfactorily  in  sealed 
tubes . 


p-Hitrobenzovl  Cnloride 

32 

P-nitrobenzoyl  chloride  is  prepared  in  the  usual  way  for 
the  preparation  of  acid  chlorides,  that  is,  by  treating  nitro- 
benzoic  acid  with  phosphorus  pentachloride 


C - OK 


C - Cl 


pels 


+ POCls  + HC1 


NO3  ^KOa 

The  reaction  goes  very  smoothly,  merely  warming  on  the 
steam-bath.  It  is  purified  by  vacuum  distillation  removing  the 
phosphorus  oxychloride  first,  by  the  same  means.  If  a rather 
high  vacuum  is  used  excellent  yields  of  the  product  are  obtained. 

Certain  precautions  are  necessary  in  the  distillation.  It 
cannot  be  distilled  with  a free  flame  because  it  decomposes  with 
explosive  violence.  An  oil  bath  in  which  the  temperature  of  the 
oil  does  not  exceed  25O0  will  serve  excellently  for  the  purpose. 

A very  short  delivery  tube  should  be  used  to  prevent  the  product 


-18- 

from  solidifying  in  it.  Care  should  be  taken  tnat  some  of  it 
does  not  go  on  through  and  clog  the  pump. 


/?Di-n-Butvl  Amino  Ethyl  p-iiitro  Benzoate  Hvdrocnloride 

/3 Di-n-butyl  amino  ethyl  alcohol  was  condensed  with  p— nitro 
benzoyl  cnloride  in  a benzene  solution  bjr  merely  mixing  and  allow- 
ing to  stand. 


C ' C1  .XUHo 

+ HOCHaCHatf<C4H 


JO2 


Cf-OCHaCHa 


•C4H9 


14 


iJ02 


Adams  and  Kamm  found  it  best  to  reflux  the  reaction  mix- 
ture. This  process  will  probably  speed  up  the  rate  of  reaction. 

It  is  rather  difficult  to  purify  oecause  its  solution  in 
alcohol  and  ethyl  acetate  is  much  given  to  supersaturation.  The 
free  base  is  an  oil  that  cannot  be  crystallized. 


/3  Di-n-Butvl  Ami  in  0 Ethyl  p-Amino  Benzoate  MoiB-nvdrochloride 
This  compound  may  be  secured  by  the  reduction  of  the  nitro 
base  by  any  one  of  several  methods. 


The  method  used  by  Einhorn  was  reduction  with  tin  and 
hydrochloric  acid.  The  tin  was  then  removed  with  hydrogen  sul- 
tide.  This  method  is  open  to  the  objection  that  it  is  very  diffi- 
cult to  remove  all  of  the  t in  and  then  the  reaction  as  a whole 


. 


- 

. 


» ' 


-19- 

does  not  go  as  cleanly  as  the  iron  reduction  that  was  used. 

Another  possibility  is  reduction  with  hydrogen  sulfide. 

This  is  open  in  a large  part  to  the  same  objections  as  the  pre- 
ceding method. 

The  method  that  was  actually  used  is  one  that  has  come  into 
general  use  only  recently.  The  hydrochloride  of  the  nitroester 
is  made  up  to  a thick  paste  with  powdered  iron  and  water.  The 
temperature  must  be  controlled  rather  carefully.  If  it  heats  up 
too  rapidly  hydrolysis  is  apt  to  take  place.  The  presence  of  too 
much  water  will  cause  hydrolysis  to  take  place. 

The  reaction  is  probably  started  by  the  action  of  the  hydro- 
chloric acid  of  the  salt.  After  that  the  action  for  the  most 
part  is  between  the  iron  arid  water.  Under  ordinary  conditions 
the  yield  should  run  from  60  per  cent  to  70  per  cent.  The  loss 
is  most  likely  due  to  hydrolysis.  The  free  base  may  be  extract- 
ed with  ether  after  treating  with  sodium  hydroxide  ana  tartaric 
acid  which  holds  the  ferrous  hydroxide  in  solution,  due  to  the 
formation  of  a complex. 

If  the  free  case  is  titrated  with  alcoholic  hydrochloric 
acid,  using  litmus. as  an  indicator,  the  mono  hydrochloride  is 
formed.  The  hydrochloric  acid  makes  the  base  soluble  and  the 
amino  group  on  the  ring  neutralizes  its  acid  properties.  The 
resulting  compound  has  marked  anesthetic  properties. 

/3  Diisobutyl  Amino  Ethyl.  o-Amino  Benz  oat,  e mono-hydro  chloride 

All  of  the  theoretical  considerations  in  the  preparation  of 

p-amino 

/^di-n-butyl  amino  ethyl /b  enzoate  mono-hydroc'nloride  are  appli- 


-20- 


I 


cable  to  this  synthesis  also.  However,  there  are  several  radical 

l e 

differences.  \ 'ihe  secondary  amine  was  prepared  by  Vein  aer  Zande's 
modification  of  the  Hofmann  method.  The  yields  were  fair  but  a 
considerable  quantity  of  the  alkyl  halide  was  not  converted,  pos- 
sibly because  the  action  was  not.  continued  long  enough.  Better 
yields  may  be  obtained  by  uniting  the  primary  amine  obtained  in 
this  manner  with  an  additional  quantity  of  alkyl  halide. 

A peculiar  thing  was  noticed  in  the  preparation  of  isobutyl 
bromide  which  is  used  as  an  intermediate.  It  was  prepared  by  the 
usual  method  for  the  preparation  of  alkyl  halides  as  developed 

33 

by  Hamm  and  marvel 

( CHg  JsCHCHaOH  + RBr  ( CHs  )2CxiCH33r  + HaO 

The  yield  was  poor  and  a large  low-boiling  fraction  was  obtained. 
This  was  probably  a constant  boiling  mixture  of  the  aiisobutyl 
ana  tertiary  butyl  bromides  . Another  interesting  feature  that 
has  not  as  yet  been  explained  is  the  fact  that  at  least  half  of 
the  good  boiling  fraction  dropped  5°  in  boiling  point  upon  stand- 
ing for  several  days. 

• 17 

Preparation  of  diisobutyl  amine  by  the  aniline  method  . The 
aniline  method  in  its  present  development  can  not  be  used  for  the 
preparation  of  diisobutyl  amine.  In  the  first  place  only  very 
small  yields  of  the  diisobutyl  aniline  caxi  be  obtained  by  the 

34 

usual  method  for  the  preparation  of  the  substituted  anilines. 
This  might  be  due  to  the  questionable  purity  of  the  isobutyl 
bromide,  but  this  is  doubtful. 

In  the  second  place,  diisobutyl  aniline  cannot  be  nitrosated 
in  the  usual  way.  Steric  hinderance  is  probably  the  cause  of  this 


' 


. 


■ 


-21- 


rather  unusual  action*  Jenkins'  has  shown  that  diisopropyl  ani- 
line acts  in  a similar  manner.  Apparently  some  of  it  did  react 
to  form  the  nitroso  compound  because  upon  refluxing  the  nitrosa- 
tion  mixture  with  sodium  hydroxide  traces  of  amine  were  actually 
obtained • 

All  of  the  other  reactions  in  the  synthesis  of  /3  diiso- 
butyl amino  ethyl  benzoate  monohydrochloride  may  be  run  in  a 
manner  similar  to  those  for  trie  preparation  of  di-n— butyl 

amino  ethyl  benzoate  monohydrochloride.  One  surprising  thing 
is  that  most  of  the  reactions  apparently  go  more  smoothly  with 
the  iso  compound  than  with  the  normal  compound. 

.Diallvlamine 

Theoretically  it  should  be  possible  to  prepare  aiallylamine 
by  the  aniline  method  but  the  literature  reports  no  attempt  to 
prepare  it  in  this  manner. 

The  diallyl  aniline  like  diisopropyl  aniline  cannot  be  suc- 
cessfully nitrosated  in  the  usual  manner.  An  oil  was  formed  but 
its  composition  was  not  determined.  Apparently  a small  amount 
of  it  was  nitrosated  because  upon  splitting  with  alkali  there  is 
no  doubt  but  that  small  amounts  of  amine  were  formed.  It  should 
be  entirely  possible  to  vary  this  method  in  sucn  a way  as  to  make 
it  available  for  the  preparation  of  diallylamine. 

r Bromopropyl  p-Hi t r ob enz  oat e 

This  compound  which  is  an  intermediate  in  the  pr eparati on  of 
the  'f  dialkylamino  propyl  esters  of  p -amino  benzoic  acid  may 
best  be  prepared  by  condensing  trimethylene  bromide  with  the 


-22- 


sodium  salt  of  nitrobenzoic  acid  using  diethylamine  as  a cata- 


lyst . 


NO  a 


+ BrCHaCHaCHaBr 


110° 


- 0CH2CH3CH2Br  + NaBr 


\ 


. 


-25- 


III  EXPERIMENTAL  PART 

j-jJitrosodi-n-Butv!ani.Line  Hydrochloride 

410  gm.  CeH.<5N(  C4H9  )a 
610  cc.  cone.  EC1 
800  cc.  water 
1^8  gm.  HaN02 

The  d i -n-buty lan i line  was  dissolved  in  the  hydrochloric 

17  0 

acid  solution  and  tne  mixture  cooled  to  below  5 » A concen- 
trated solution  of  sodium  nitrite  was  slowly  added  through  a 
dropping  funnel.  This  addition  should  take  from  an  hour  to  an 

hour  and  a half.  The  reaction  mixture  was  stirred  mechanically 

0 

and  the  temperature  was  not  allowed  to  rise  aoove  5 during  the 
reaction. 

The  reaction  mixture  became  an  orange  red  at  first  but  as 
the  reaction  proceeded  the  color  deepened  until  at  the  end  it 
was  almost  black.  At  the  completion  of  the  reaction  the  mixture 
was  allowed  to  come  to  room  temperature  and  the  product  was  fil- 
tered out  and  dried.  The  yield  was  462  grams  or  85.3  per  cent 
of  the  theory.  On  another  typical  run  the  yield  was  increased 
to  490  grams  or  90  per  cent  of  the  theory. 

When  moist  the  nitroso  compound  was  a buff  color,  but  upon 
drying  became  yellow  green.  It  was  purified  by  precipitation 
from  an  alcohol  solution  with  ether.  This  procedure  often  gave 
a tarry  substance  that  would  not  crystallize.  It  was  also  puri- 
fied by  washing  with  hot  acetone.  The  pure  compound  crystallized 


-24- 


o 

out  in  the  form  of  yellow  green  needles  that  melted  at  107  * If 
it  is  planned  to  store  any  of  this  compound  it  should  be  stored 
as  the  free  base  and  not  as  the  hydrochloride  because  the  latter 
decomposes  into  a tarry-like  mass  upon  standing  for  any  great 
length  of  time. 

For  the  preparation  of  di-n-butyl  amine  it  was  found  that 
the  crude  product  would  work  satisfactorily  so  it  was  not  puri- 
fied. In  many  cases  it  was  not  even  dried  and  weighed  but  a 
90  per  cent  yield  was  assumed  and  the  yield  o.f  di-n-butyl  amine 
calculated  upon  that  basis. 

Di-n-butyl  Amine 

270.9  gm.  p-NO  -CeH4-U0C4H«  )aHCl 
120  gin,  UaOK 
3200  cc . water . 

Enough  sodium  h3rdr  oxide  to  make  an  excess  of  one  mole  was 
used.  Sufficient  water  was  added  to  form  a 2 l/2  per  cent  sol- 
ution of  the  alkali  after  the  hydrochloric  acid  had  teen  neutral- 
ized. After  refluxing  for  a short  time  an  oily  layer  with  a 

IV 

dark  blue  cast  formed  on  top  . This  was  the  free  case.  The 
mixture  was  refluxed  for  10  hours  and  then  distilled  through  a 
Clarke  separator  for  an  additional  10  hours.  The  yield  was  6 0.99 
grams  or  47.9  per  cent  of  the  theory.  This  was  not  figured  on 
the  basis  of  the  crude  amine  but  upon  the  pure  product.  On  an- 
other run  during  which  the  mixture  was  refluxed  for  9 hours  and 
distilled  through  the  Clarke  separator  for  6 hours*  a 49  per  cent 
yield  was  obtained. 

Toward  the  end  of  the  run  the  water  returning  to  the  distill' 


ijv  K*  . 


' 


' 


. * ■ 


-25- 

3 8 

ing  flask  through  the  Clarke  separator  still  contained  traces 
of  amine,  but  it  was  found  unprofitable  to  v/ork  it  for  the  ad- 
ditional amine  that  might  be  obtained.  A certain  amount  of 
ta.rry  material  was  formed  during  the  refluxing.  It  was  proba- 
bly formed  by  a side  reaction  of  the  alkali  upon  the  nitroso 
compound. 

The  amine  was  dried  with  sodium  hydroxide  and  distilled, 

o o 

the  fraction  boiling  between  157  and  161  being  collected 
(correct  B.P.  159°)  * It  is  a cle  ar  liquid,  lighter  than  water, 
gradually  turning  yellow  upon  standing.  The  odor  is  strongly 
ammoniacal . 

Several  precautions  in  procedure  might  be  noted:  ( 1 ) Do  not 
attempt  to  dry  the  amine  with  calcium  chloride,  use  sodium  hy- 
droxide; (2)  do  not  use  rubber  stoppers,  but  cork  stoppers  seal- 
ed in  with  sodium  silicate. 

Ethvlene  Oxide 

80.5  gm.  CHaOHCHsCl 
80  gm.  NaOH 

The  sodium  hydroxide  was  s lowly  added  to  the  ethylene 

3 1 

chlorohydrin  through  a dropping  funnel  . A saturated  solution 
containing  an  excess  of  one  mole  was  fouiid  to  give  the  best  re- 
sults. The  generating  flask  was  heated  until  it  was  warm  to  the 
touch.  An  evolution  of  the  gas  started  almost  immediately  and 
sodium  chloride  precipitated  out. 

The  ethylene  oxide  was  condensed  by  passing  it  through  a 
spiral  ice  condenser  and  was  collected  in  tubes  packed  in  ice. 


-26- 


The  tubes  were  then  sealed  off.  The  yield  was  21.6  grams  or 

49*2  per  cent  of  the  theory  . On  another  typical  run  a yield  of 

52  per  cent  was  obtained.  The  product  was  a colorless  liquid 

0 

boiling  at  12.0* 

Precautions:  ( 1 ) Do  not  heat  the  generating  flask  too  hot; 

(2)  Have  several  tubes  prepared  for  collecting  the  product  because 
condensation  proceeds  very  rapidly  after  it  has  once  started. 

(3)  It  is  not  necessary  to  dry  the  product  if  it  is  to  be  con- 
densed with  an  amine  because  the  presence  of  moisture  is  essen- 
tial in  this  reaction. 

/3  Di-n-butvl  Amino  Ethyl  Ale  ohol 

5 01  gm.  CH3CH2 
0 

150  gm*  (C4H9  )aHH 

The  ethylene  oxide,  sealed  in  a small  tube,  was  placed  in  a 
large  tube  with  the  di-n-butyl  amine  and  the  large  tube  sealed 

30 

off  . The  smaller  tube  was  then  broken  by  shaking  and  the  mix- 
ture allowed  to  stand  for  an  hour  after  which  it  was  placed  in 
the  steam  bath  for  5 hours.  The  tube  was  then  opened  and  the 
product  distilled. 

B.  P.  142°  - 145°  at  55  mm.;  225°  - 230°  with  slight  decom- 
position at  760  mm.  Yield  19>2  grams  or  92  l/2  per  cent  of  the 
theory.  The  loss  probably  occurred  in  handling,  because  only 
traces  of  low  and  high  boiling  fractions  were  obtained.  On  other 
typical  runs  the  same  high  yields  were  consistently  obtained. 

The  unpurified  alcohol  was  a light  reddish  brown  in  color 


-27- 

but  the  pure  product  w&s  colorless  and  slightly  viscous.  It  hac 
a faint  ammoniacal  odor. 

The  ethylene  oxide  should  not  be  dried  before  use,  or  if 
it  has  been  dried  previously  a drop  of  water  should  be  added, 
since  the  condensation  does  not  run  smoothly  if  both  of  the 
reacting  substances  are  dry. 

/3  Di-n-butvl  Amino  Ethyl  o-N i t r ob  e nz  oa t e Hydrochloride 

20  gm.  ( C4H0 )aNCHaCHaOH 
21.4  gm.  p-i;03CeH4C0Cl 
500  cc.  benzene 

The  p-nitrobenzoyl  chloride  was  dissolved  in  the  benzene 

1 + 

and  the  alcohol  added  . The  solution  turned  yellow  and  warmed 
up  slightly  after  which  it  was  warmed  on  the  steam  bath  and 
allowed  to  stand.  After  an  hour  the  ester  began  to  form  in 
flakes  throughout  the  solution.  Within  30  minutes  more  the  sol- 
ution had  almost  solidified.  The  precipitate  was  filtered  out 
and  dried.  Yield  - 2)  grams  or  56  per  cent  of  the  theory. 

The  filtrate  was  allowed  to  stand  for  several  hours  and 
then  the  remainder  of  the  ester  was  obtained  as  a heavy  oil, 
upon  evaporation  of  the  benzene.  This  oil  solidified  after 
standing  for  several  days.  This  brought  the  yield  up  to  theore- 
tical. Probably  refluxing,  as  advised  Adams  and  Kamm,  would 
have  speeded  up  the  reaction. 

The  hydrochloride  of  the  ester  which  is  obtained  in  this 
reaction  resembles  soap  very  much  in  appearance  and  melts  at 
88°-89°.It  is  very  difficult  to  purify  because  its  solution  is 


-28- 


much  given  to  supersaturation.  The  best  method  for  its  purifi- 
cation is  to  re c rystallize  from  absolute  alcohol  and  ethyl  ace- 
tate. Even  after  recrystallizing  a second  time  the  product  re- 
mained slightly  sticky.  The  free  case  is  a light  yellow  oil  that 
cannot  be  crystallized. 

/3Di-n-butvl  Amino  Ethyl  p -Amino benz oate  ikono-hvdrochloride 
27.5  gm.  p— NOa CeH*  COOCHa CH3xI(  C4H9  )HC1 
75  gm.  powdered  iron. 

The  nitro-ester  and  powdered  iron  were  mixed  together  with 
just  enough  water  to  make  a ve.ty  thick  paste.  After  a short  time 
the  mixture  began  to  warm  up.  The  temperature  was  controlled 
by  placing  the  beaker  in  an  ice  bath  and  during  the  reduction  the 
mixture  was  constantly  stirred.  After  an  hour,  when  the  reaction 
had  practically  ceased,  a small  additional  amount  of  iron  was 
added  and  the  mixture  warmed  for  a short  time  on  the  steam  bath. 

An  excess  of  tartaric  acid  solution  was  added  and  then  the 
solution  was  made  alkaline  with  sodium  hydroxide.  The  iron  was 
then  filtered  out  and  bot b the  iron  residue  and  the  solution  ex- 
tracted with  ether.  Upon  evaporating  the  ether  the  amino  ester 
was  obtained  as  a heavy  oil.  Yield  14  grams  or  62.5  per  cent, 
of  the  theory.  On  other  runs  the  yield  was  raised  to  70  per  cent. 
The  oil  was  dissolved  in  alcohol  and  titrated  to  neutrality  with 
alcoholic  hydrochloric  acid,  using  ±itmus  as  an  indicator.  Upon 
concentrating  tne  alcoholic  solution  the  product  crystallized  out 
in  needle-like  crystals.  It  may  be  purified  by  recrystallization 

from  absolute  alcohol  and  ethyl  acetate  or  from  water. 

o , 0 

The  hydrochloride  of  the  ester  melts  at  167-  169 • 


-29- 


Diisobutvl  Amine 
51  gm.  (CHs  )2CHCH3Br 

70  gm.  15  per  cent  alcoholic  iiHa  | 

The  15  per  cent  alcoholic  ammonia  solution  was  made  by  sat- 

l e 

urating  alcohol  with  ammonia  . The  mixture  of  isobutyl  bromide 
and  alcoholic  ammonia  was  sealed  in  a tube  and  heated  in  the 
water  bath  for  60  hours.  A white  precipitate  slowly  formed. 

This  precipitate  was  later  proven  to  be  ammonium  bromide.  It  was 
filtered  out  and  the  amine  hydrobromide  obtained  upon  the  dis- 
tillation of  the  alcohol. 

A mixture  of  primary,  secondary,  and  tertiary  amines  was 
obtained  upon  treating  the  hydrobromide  salt  with  sodium  hydrox- 
ide. The  secondary  amine  was  separated  from  the  mixture  by  frac- 
tionation. Yield  -4.3  gm.  or  10  per  cent  of  the  theory.  Diiso- 

butylamine  is  a colorless  liquid  with  an  ammoniacal  odor,  is 

0 0 

lighter  than  water  and  boils  at  139  - 140  . 

4?-£)iisobutvl  Amino  Ethvl  Ale ohol 

1.1  gm.  CH3CH3 

0 

3.2  gm.  ( ( CHs  )aCHCH2  )a  NH 

The  details  of  the  reaction  are  exactly  the  same  as  in  the 
case  of  the/?di-n-butyl  amino  ethyl  alcohol.  The  mixture  was  heat- 
ed for  10  hours.  Yield  3 »2  grams  of  75  per  cent  of  the  theory. 

The  low  yield  was  probably  due  to  the  fact  that  small  amounts 

0 0 

were  used.  The  alcohol  boils  at  212  - 215  which  checks  with 

the  boiling  point  reported  by  Matthes.  Einhorn  reports  a boiling 


-31- 


of  trimethylene  bromide,  using  dietnylamine  as  a catalyst*  It 

o 

was  heated  from  6 to  8 hours  at  a temperature  of  110  . The  tem- 
perature of  the  oil  bath  should  be  carefully  regulated  to  pre- 
vent its  temperature  going  above  this  point. 

At  the  end  of  this  refluxing  the  excess  of  trimethylene 
bromide  was  removed  by  vacuum  distillation.  The  bromester  was 
then  removed  from  the  sodium  bromide  by  extraction  with  ether. 

An  effort  was  next  made  to  purify  it  oy  vacuum  distillation  but 
due  to  a mishap  to  the  vacuum  system  it  became  badly  charred 
and  the  distillation  had  to  oe  abandoned.  The  charred  mass  was 
extracted  with  ether  and  some  of  the  product  was  recovered.  It 
may  be  purified  by  recrystallization  from  alcohol. 

In  the  last  vacuum  distillation  it  is  aosoiutely  essential 
that  the  pressure  be  reduced  to  at  least  5 run.  The  distilling 
flask  should  be  fitted  with  a large  side  arm  and  should  be  set 
as  low  as  possible  in  tne  oil  bath.  It  would  be  advisable  to 
have  a wire  extend  through  the  side  arm,  to  serve  as  a heat  con- 
ductor and  in  this  way  prevent  tne  clogging  of  the  side  arm. 

Unsuccessful  Attempts  to  Prepare  Secondary  Amines. 

Application  of  the  aniline  method  to  the  preparation  of 
diisobutyl  and  d daily 1 • amines . 

hi  is  obutyl  Aniline: 

60  gm.  CeHeHHa 
226  gm.  ( CHs )aCHCHaBr 
6 0 gm.  NaOH 

Half  of  the  isobutyl  bromide  was  added  to  tne  aniline  and 


. , ' >■ 


- * 


~ i.  V,  J 


. . 


. . 1 . . 


■ 


w ' ■ t W » - , , 


J 


— ... 


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• ' . J ' i 


- 


. 


. ..  . 


• ' ...  . . . 


• - 1 • • - ' . * , ,V  jI 


V.  . . 


; - 


. 


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* • . . 


J - 


’ ; , 


^ » / 


«.  • 1 


...  .. 


. 

: 


.......  ..  . 


v,r  .. 


-32- 


t he  mixture  refluxed  for  12  hours.  The  remainder  of  the  isobutyl 
bromide  and  the  sodium  hydroxide  were  added  and  the  mixture  again 
refluxed  for  12  hours.  The  product  was  then  dried  and  distilled. 


weighed  20  grams,  15  per  cent  of  the  theory. 

p-.Nitr  oso-diisobuty  1 aniline  hydrochloride . An  attempt  was  I 
made  to  prepare  this  compound  using  tne  same  procedure  and  the  j 
same  proportions  as  in  the  case  of  p-nitr oso-di-n-butyl  aniline 
hydrochloride . An  oil  was  formed  and  all  attempts  to  crystallize  I 
it  failed. 

Diisobutyl  Amine.  The  oil  obtained  above  was  treated  in 
exactly  the  same  way  as  the  p-nitr  oso-di-n-butyl  aniline  h3raro- 
chloriae  in  the  preparation  of  di-n-butyl  amine . Only  traces  of 
the  amine  were  obtained. 

Diallyl  amine.  The  same  procedure  as  above  was  carried  out  j 
on  diallyl  aniline  with  the  same  results,  only  traces  of  the  j 

amine  being  formed.  i 

Attempt  to  Prepare  Di-n-butvi  Amine  bv  the  Sulfonamide  method 


The  toluene  sulfonamide  was  prepared  by  treating  toluensul- 
fonjrl  chloride  with  ammonium  hydroxide.  The  toluene  sulfonamide 
and  butylbromide  were  dissolved  in  the  alcohol,  a 40  per  cent 
solution  of  half  of  the  alkali  added  and  the  mixture  refluxed 


u 0 

It  boiled  between  160  and  250  . Diisobutyl  aniline  boils  at 

0 o 00 

240  - 245  . The  fraction  that  boiled  between  255  and  245 


85.5  gm.  P-CH3C0H4SO3NH3 


157  gm.  C4K9Br 


40  gm.  i^aOH 


500  cc.  alcohol 


I 


...  « 


v 1 


' 


V.  » 


- 

*-j  o> 


• - 


. . . 


' . 11  1 ( 


. 


* 


<'  , ■}  . >.  I 


1.'.. 


• v 


. 


: ' 


r 


v ..  . c 


-33- 


until  it  became  neutral.  This  required  4 hours.  The  reminder 
of  the  alkali  was  added  and  the  mixture  again  refluxed  until  it 
became  neutral.  This  required  9 hours. 

The  ale dhol  was  then  distilled  off  and  the  sodium  bromide 
removed  with  water.  An  attempt  was  made  to  purify  the  toluene 
sulf ondibutylarnide  by  vacuum  distillation.  The  vacuum  failed 
and  the  product  charred  instantly.  The  method  was  then  abandon- 
ed in  favor  of  the  aniline  method. 


-34- 


IV  SUMMARY 

1.  The  chief  theories  for  local  anesthesia  have  oeen  Uriel - 
ly  discussed. 

2.  Available  methods  for  preparing  secondary  amines  have 
been  discussed  with  respect  to  their  relative  merits. 

3.  The  best  conditions  for  the  preparation  of  di-n-butyl 
amine  have  been  determined. 

4.  A method  for  the  preparation  of  di—n— butyl  and  /3  diiso— 

butyl  amino  ethyl  alcohol  oy  the  condensation  of  the  correspond- 
ing amine  with  ethylene  oxide  has  been  worked  out.  This  is  un- 
questionably the  best  method  for  the  production  of  these  alcohols 

5*  /3  di-n-butyl  and  /f?diisooutyl  amino  ethyl  p-amino  ben- 
zoate hydrochlorides  have  been  prepared.  These  compounds  show 
marked  anesthetic  power. 

6.  It  has  been  shown  that  diisobutyl  and  diallylaniline 
cannot  be  nitrosated  in  the  usual  way.  It  follows  then  that 
the  corresponding  secondary  amines  cannot  be  prepared  by  the  ani- 
line method. 


-35- 


V BIBLIOGRAPHY 

1.  Jenkins  - University  of  Illinois  Thesis  (1921) 

2.  Feet  - University  of  Illinois  Thesis  (1921) 

3»  Verworn  - "Irritability"  (1913) 

4.  Burge  - Amer.  Jour,  of  Physiol*  45.,  38S  (1918) 

5*  Mathews  - Intern.  Zeit.  Physik..  Biologie  I,  432-449  (1914) 

6.  Ehrlich  - Revue  General  de  Chemie  14,  93  (1911) 

7*  Lillie  - Science,  1Z>  764-67;  959-72  (1913) 

8.  Osterhout  - Proceedings  Arner.  Physiol.  Soc.  (1911) 

Amer.  Jour.  Physiol.,  25,  11 

9*  Harvey  - Bull.  Carnegie  Inst.,  Vol.  11  Pt . 4 ( 1915  ) 

10.  Traube  - Biochem.  Zeit.  177  (191) 

11.  Clowes  - Proces.  Soc.^xP*  Biol,  and  Med.  llr  8-10. 

12.  Overtoil  and  Meyer  - "Studien  tioer  die  Markose"  (1901) 

13.  Einhorn  - Annalen  371.  125-179  (1910) 

14.  Adams  and  Kamm  - Jour.  Amer.  Chem.  Soc.,  12,  IO3O-53  (1920) 

U.  S.  Pat.  1,  358,  750;  1,  358,  751  (1920) 

Chem.  Abs.,  15,  412  (1921) 

15.  Hofmann  - Jour.  Chem.  Soc.,  1,  300  (l84.r9) 

16.  Van  der  Zanae  - Rec . T^av.  Chirn.  8,  202-214  ( 1889  ) 

17.  Reilly  and  Hickinbottom  - Jour.  Chem.  Soc.,  T,  112,  99-111(1918) 

18.  Marckwala  and  Freiherr  - D.R.P.  105,  87 0 Winther  1°6 

19*  Traube  and  Engelhardt  - D.R.P.  17205:  Friedlander  H,  ill  (1913 

Ber.  41,  3149-3152  (1911) 

20.  L&ffler  - Ber.,  4£,  203x-5  (1910) 

21.  Mailhe  - Compt.  Rend.,  JH,  113-115: ( 1906  ) 140.  1691-92(1905  ) 

22.  Sabatier  and  Senderens  - Compt.  Rend  140.  1691-92  (1905) 

23.  Sabatier  and  Mailhe  - Compt.  Rend.  148,  898-901  ( 1909  ) 


...  ) 


t 


i 


% - . 


-36- 


24.  Merz  and  Gasiorowski  - Ber.,  17.  623-640  (1884) 

25.  Von  Braun  - Ber.,  3209-20  (1910). 

26.  Bayer  Co.,  - D.R.P.,  269430  Friedlander  11,  114-3  (1913) 

27*  Werner  - Hour.  Chem.  Soc.,  111.  844-33  ( 1917  ) 

28.  Clarke  - Jour.  Ainer.  Chem.  Soc.,  itj,  3 66  (1921) 

29.  Ladenburg  - Ber.,  l±y  2406-2409  ( l8Sl ) 

30.  Matthes  - Annalen  ^16.  3II-317  (1901)  Ber.,  jit,  3482-84(1901; 

31.  Badische  Anilin  and  Soda  Fabrik  - D.R.P.,  299,  682 

Cnem.  Zentr.  .91  Pt.  4,  16  (1920) 

32.  Franklana  - Jour,  Chem.  Soc.,  T 85,  1376  (1904) 

33*  Kamm  and  Marvel  - Jour.  Amer.  Chem.  Soc.,  i±2,  299-309  (1920  ) 
34.  Zander  - Annalen  214,  149-170 

35  * D.  R.P.  179627,  180291,  180292,  194748,  172568,  189335, 

194365  - Friedlander  VIII  993-1010. 


